The Burnham Center for Chemical Genomics, with a strong track record in the MLSCN phase and impressive institutional support, is poised to contribute to the Molecular Libraries Probe Production Centers Network (MLPCN) as a Comprehensive Screening Center. The Burnham Center is probably the most diverse of all Network Centers, offering not only basic HTS and uHTS capabilities and outstanding medicinal chemistry, but also (i) advanced development of phenotypic screens based on multi-spectral high throughput microscopy (HTM); (ii) microfluidics technology for rapid multi-parallel synthesis of compound analogues; (iii) strong capabilities in NMR-based compound optimization using fragment-based approaches; (iv) advanced 3D computational modeling and structure-based compound optimization capabilities; and (v) exploratory pharmacology. In preparation for the MLPCN Phase, additional institutional support was provided for expanding the capabilities of the Center, including an additional uHTS system. Altogether, the Burnham Center stands ready to advance the mission of the NIH Roadmap into full Production Phase. The Burnham Center is organized into 5 Units that support the User-driven goals of MLPCN, and 2 Center-driven projects aimed at advancing the field of chemical genomics in an integrated manner. Supporting MLPCN's core mission are the following Units: (1) Assay development, adaptation and implementation, which includes world-class expertise in high-content (HC) assay and software development; (2) HTS, ready to handle now the throughput and diversity of HTS demands of MLPCN, with capacity to expand for meeting any future throughput demands; (3) Chemistry, which includes integrated subunits devoted to (a) medicinal chemistry, (b) cheminformatics, (c) NMR-based technologies for compound validation and optimization, and (d) exploratory pharmacology; (4) Informatics, with a powerful supporting relational database with links to > 8 million commercially available compounds and multi-Terabyte archiving capacity for supporting HC applications; and (5) Administration. The infrastructure for accomplishing these goals was established during the MLSCN phase, including all aspects of data and resource sharing; collaborative interactions with assay providers, other Network Centers and NIH; inter-institutional IP management; and internal Center governance, thus positioning our Center to deliver results immediately. The Center-driven projects focus on: (1) applications of continuous-flow microreactor technology for addressing the medicinal chemistry bottleneck, reducing the time and costs of compound analoging to a fraction of current standards; and (2) development of advanced SD-imaging technologies for HC screening (HCS), including (a) 3D cell culture systems; (b) innovative HTM instrumentation; and (c) novel imaging algorithms and software, which will enable a new generation of chemical genomics applications that push technology applications beyond monolaver cell cultures.